Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical Research

Hypoxia and exercise interactions on skeletal muscle insulin sensitivity in obese subjects with metabolic syndrome: results of a randomized controlled trial



Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome.


In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO2 conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO2 21%) conditions or hypoxia (n = 12; FiO2 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual V̇O2max. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues.


The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISIClamp: 0.035 (IQR 0.016–0.075) vs. 0.037 (IQR 0.026–0.056) mg* kg−1 *min−1/(mU* l−1); p = 0.767). In contrast, ISIClamp improved during hypoxia training (0.028 (IQR 0.018–0.035) vs. 0.038 (IQR 0.024–0.060) mg * kg−1 *min−1/(mU *l−1); p < 0.05). Between group comparison of ISIClamp change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISIClamp during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISIClamp during hypoxic training.


Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2: ISIClamp before and after a moderate 6-week training under either normobaric normoxic (n = 9) or hypoxic (n = 12) conditions.
Fig. 3: Adipose NPR-A/NPR-C ratio before and after a moderate 6-week training under either normobaric normoxic (n = 9) or hypoxic conditions (n = 12).
Fig. 4

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


  1. 1.

    Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care. 2002;25:1135–41.

    Article  Google Scholar 

  2. 2.

    Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002;25:1177–84.

    Article  Google Scholar 

  3. 3.

    Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391:541–51.

  4. 4.

    Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, Bantle J, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012;308:2489–96.

    CAS  Article  Google Scholar 

  5. 5.

    Yassine HN, Marchetti CM, Krishnan RK, Vrobel TR, Gonzalez F, Kirwan JP. Effects of exercise and caloric restriction on insulin resistance and cardiometabolic risk factors in older obese adults-a randomized clinical trial. J Gerontol A Biol Sci Med Sci. 2009;64:90–5.

    Article  Google Scholar 

  6. 6.

    VDB JD, VDV JHPM, DEW EAC, Bosma H, Savelberg H, Schaper NC, et al. Replacement effects of sedentary time on metabolic outcomes: The Maastricht Study. Med. Sci. Sports Exerc. 2017;49:1351–8.

    Article  Google Scholar 

  7. 7.

    Moreno-Franco B, Penalvo JL, Casasnovas Lenguas JA, Leon-Latre M. [Compliance with Physical Activity Recommendations and Associated Factors in a Cohort of Spanish Adult Workers]. Rev Esp Salud Publica. 2015;89:447–57.

    Article  Google Scholar 

  8. 8.

    Harrison RA, Roberts C, Elton PJ. Does primary care referral to an exercise programme increase physical activity one year later? A randomized controlled trial. J Public Health (Oxf). 2005;27:25–32.

    Article  Google Scholar 

  9. 9.

    Tjonna AE, Lee SJ, Rognmo O, Stolen TO, Bye A, Haram PM, et al. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation. 2008;118:346–54.

    Article  Google Scholar 

  10. 10.

    Hamlin MJ, Lizamore CA, Hopkins WG. The effect of natural or simulated altitude training on high-intensity intermittent running performance in team-sport athletes: a meta-analysis. Sports Med. 2018;48:431–46.

    Article  Google Scholar 

  11. 11.

    Czuba M, Wilk R, Karpinski J, Chalimoniuk M, Zajac A, Langfort J. Intermittent hypoxic training improves anaerobic performance in competitive swimmers when implemented into a direct competition mesocycle. PLoS ONE. 2017;12:e0180380.

    Article  Google Scholar 

  12. 12.

    Haufe S, Wiesner S, Engeli S, Luft FC, Jordan J. Influences of normobaric hypoxia training on metabolic risk markers in human subjects. Med. Sci. Sports Exerc. 2008;40:1939–44.

    Article  Google Scholar 

  13. 13.

    Wiesner S, Haufe S, Engeli S, Mutschler H, Haas U, Luft FC, et al. Influences of normobaric hypoxia training on physical fitness and metabolic risk markers in overweight to obese subjects. Obesity. 2010;18:116–20.

    CAS  Article  Google Scholar 

  14. 14.

    Klug L, Mahler A, Rakova N, Mai K, Schulz-Menger J, Rahn G, et al. Normobaric hypoxic conditioning in men with metabolic syndrome. Physiol Rep. 2018;6:e13949.

    Article  Google Scholar 

  15. 15.

    Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551–78.

    CAS  Article  Google Scholar 

  16. 16.

    Ameln H, Gustafsson T, Sundberg CJ, Okamoto K, Jansson E, Poellinger L, et al. Physiological activation of hypoxia inducible factor-1 in human skeletal muscle. FASEB J. 2005;19:1009–11.

    CAS  Article  Google Scholar 

  17. 17.

    Lolmede K, Durand de Saint Front V, Galitzky J, Lafontan M, Bouloumie A. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord. 2003;27:1187–95.

    CAS  Article  Google Scholar 

  18. 18.

    Gustafsson T. Vascular remodelling in human skeletal muscle. Biochem Soc Trans. 2011;39:1628–32.

    CAS  Article  Google Scholar 

  19. 19.

    Mandroukas A, Metaxas TI, Heller J, Vamvakoudis E, Christoulas K, Riganas CS, et al. The effect of different exercise-testing protocols on atrial natriuretic peptide. Clin Physiol Funct Imaging. 2011;31:5–10.

    Article  Google Scholar 

  20. 20.

    da Silveira Campos RM, Damaso AR, Masquio DCL, Duarte FO, Sene-Fiorese M, Aquino AE Jr., et al. The effects of exercise training associated with low-level laser therapy on biomarkers of adipose tissue transdifferentiation in obese women. Lasers Med Sci. 2018;33:1245–54.

    Article  Google Scholar 

  21. 21.

    Zhang QL, Cui BR, Li HY, Li P, Hong L, Liu LP, et al. MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria. Biochem. Biophys. Res. Commun. 2013;438:507–12.

    CAS  Article  Google Scholar 

  22. 22.

    Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–97.

  23. 23.

    Mai K, Andres J, Bobbert T, Maser-Gluth C, Mohlig M, Bahr V, et al. Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue. Clin Endocrinol. 2007;67:419–25.

    CAS  Article  Google Scholar 

  24. 24.

    DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–23.

    CAS  PubMed  Google Scholar 

  25. 25.

    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    CAS  Article  Google Scholar 

  26. 26.

    Toka O, Tank J, Schachterle C, Aydin A, Maass PG, Elitok S, et al. Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly. Hypertension. 2015;66:800–8.

    CAS  Article  Google Scholar 

  27. 27.

    Haftenberger M, Schuit AJ, Tormo MJ, Boeing H, Wareham N, Bueno-de-Mesquita HB, et al. Physical activity of subjects aged 50-64 years involved in the European Prospective Investigation into Cancer and Nutrition (EPIC). Public Health Nutr. 2002;5:1163–76.

    CAS  Article  Google Scholar 

  28. 28.

    Chobanyan-Jurgens K, Scheibe RJ, Potthast AB, Hein M, Smith A, Freund R, et al. Influences of hypoxia exercise on whole body insulin sensitivity and oxidative metabolism in older individuals. J Clin Endocrinol Metab. 2019;104:5238–48.

  29. 29.

    Brachs M, Wiegand S, Leupelt V, Ernert A, Kintscher U, Jumpertz von Schwarzenberg R, et al. ANP system activity predicts variability of fat mass reduction and insulin sensitivity during weight loss. Metabolism. 2016;65:935–43.

    CAS  Article  Google Scholar 

  30. 30.

    Gorgens SW, Benninghoff T, Eckardt K, Springer C, Chadt A, Melior A, et al. Hypoxia in combination with muscle contraction improves insulin action and glucose metabolism in human skeletal muscle via the HIF-1alpha pathway. Diabetes. 2017;66:2800–7.

    Article  Google Scholar 

  31. 31.

    Slivka DR, Heesch MW, Dumke CL, Cuddy JS, Hailes WS, Ruby BC. Human skeletal muscle mRNAResponse to a single hypoxic exercise bout. Wilderness Environ Med. 2014;25:462–5.

    Article  Google Scholar 

  32. 32.

    De Smet S, D'Hulst G, Poffe C, Van Thienen R, Berardi E, Hespel P. High-intensity interval training in hypoxia does not affect muscle HIF responses to acute hypoxia in humans. Eur J Appl Physiol. 2018;118:847–62.

    Article  Google Scholar 

  33. 33.

    Lundby C, Gassmann M, Pilegaard H. Regular endurance training reduces the exercise induced HIF-1alpha and HIF-2alpha mRNA expression in human skeletal muscle in normoxic conditions. Eur J Appl Physiol. 2006;96:363–9.

    CAS  Article  Google Scholar 

  34. 34.

    Lindholm ME, Rundqvist H. Skeletal muscle hypoxia-inducible factor-1 and exercise. Exp Physiol. 2016;101:28–32.

    CAS  Article  Google Scholar 

  35. 35.

    Trayhurn P, Wang B, Wood IS. Hypoxia and the endocrine and signalling role of white adipose tissue. Arch Physiol Biochem. 2008;114:267–76.

    CAS  Article  Google Scholar 

  36. 36.

    Wagner H, Fischer H, Degerblad M, Alvarsson M, Gustafsson T. Improvement of insulin sensitivity in response to exercise training in type 2 diabetes mellitus is associated with vascular endothelial growth factor A expression. Diab Vasc Dis Res. 2016;13:361–6.

    CAS  Article  Google Scholar 

  37. 37.

    Solomon TP, Haus JM, Li Y, Kirwan JP. Progressive hyperglycemia across the glucose tolerance continuum in older obese adults is related to skeletal muscle capillarization and nitric oxide bioavailability. J Clin Endocrinol Metab. 2011;96:1377–84.

    CAS  Article  Google Scholar 

  38. 38.

    Schlueter N, de SA, Willmes DM, Spranger J, Jordan J, Birkenfeld AL. Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome. Pharmacol Ther. 2014;144:12–27.

    CAS  Article  Google Scholar 

  39. 39.

    Sun JZ, Oparil S, Lucchesi P, Thompson JA, Chen YF. Tyrosine kinase receptor activation inhibits NPR-C in lung arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2001;281:L155–63.

    CAS  Article  Google Scholar 

  40. 40.

    Rudvik A, Mansson M. Evaluation of surrogate measures of insulin sensitivity - correlation with gold standard is not enough. BMC Med Res Methodol. 2018;18:64.

    Article  Google Scholar 

Download references


We thank Gabriele Rahn, N. Huckauf, and C. Kalischke for excellent technical assistance.


This research was supported by the Deutsche Forschungsgemeinschaft (LU 435/13-1). KM was supported by the German Diabetes Society (DDG) and the German Ministry for Education and Research (BMBF) by support of the Berlin Institute of Health (BIH).

Author information




NR, MB, LK, AM, TB, and JSM researched data. KM researched data and was primarily responsible for writing the manuscript. TB, MB, SP, AM, LK, JS, and FCL contributed to the discussion and reviewed/edited the manuscript. FCL conceived the study and obtained funding.

Corresponding author

Correspondence to Knut Mai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study protocols were approved by the Institutional Review Board of the Charité Medical School (EA1/140/12) and all subjects gave written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mai, K., Klug, L., Rakova, N. et al. Hypoxia and exercise interactions on skeletal muscle insulin sensitivity in obese subjects with metabolic syndrome: results of a randomized controlled trial. Int J Obes 44, 1119–1128 (2020).

Download citation

Further reading


Quick links